Project Summary Influenza A pneumonia is the most common cause of death from an infectious agent in older patients. While the lung is the primary target of the influenza A virus, the resulting illness is characterized by dysfunction in multiple organs. Skeletal muscle weakness is an important manifestation of the systemic consequences of influenza A virus infection (IAV) and is manifest in approximately half of the patients admitted to the intensive care unit with respiratory failure. This weakness can persist for years after hospital discharge and it is a major contributor to morbidity. We present preliminary data suggesting that endocrine signals released from the injured lung both induce and protect against skeletal muscle dysfunction during influenza A infection. We hypothesize that the frailty of the proteostasis networks in the muscles of aged mice shifts this balance, resulting in enhanced skeletal muscle dysfunction. Thus, we propose via three interrelated aims, to elucidate the signaling pathways regulating skeletal muscle degradation and proteostasis during influenza A pneumonia: in Specific Aim # 1, we propose to determine whether influenza A infection causes disruption in muscle proteostasis via IL-6, STAT3, FOXO3 and atrogin1 dependent degradation of skeletal muscle; in Specific Aim # 2, we propose to assess whether in aged mice influenza A infection causes AMPK activation and thus inhibition of mTOR which leads to impaired proliferation/differentiation of satellite cells and recovery and in Specific Aim # 3, we will determine whether modulating the chaperone response can improve muscle function in aged mice. We have conducted experiments for each of the specific aims, and the preliminary data support the feasibility of this proposal. Completion of the proposed research will provide novel, clinically relevant information regarding the effects of influenza A infection on myoproteostasis. This novel information is of biologic and clinical relevance and should lead to the design of innovative approaches to improve proteostasis and skeletal muscle function in older patients with influenza A infection.